Applying Synthetic Lethality for the Selective Targeting of Cancer

• Published in: The New England journal of medicine Vol. 371; no. 18; pp. 1725 - 1735
• Main Authors: McLornan, Donal P, List, Alan, Mufti, Ghulam J
• Format: Journal Article
• Language: English
• Published: Waltham, MA Massachusetts Medical Society 30.10.2014
• Subjects: Antineoplastic Agents - therapeutic use; Apoptosis; Biological and medical sciences; Cancer; Cell death; Deoxyribonucleic acid; DNA; DNA Repair; Drug Discovery; General aspects; Genes, Lethal; Genes, myc; Humans; Kinases; Lethality; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Neoplasms - genetics; Neoplasms - therapy; Poly(ADP-ribose) Polymerase Inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Tumors; Medicine; Malignant tumor; Cancer
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJMra1407390

Synthetic lethality refers to the requirement that two defects be present for cell death to occur. When an agent damages DNA, its effects on the cell can be amplified if the efforts of the cell to repair the damage are inhibited. Clinical application of this idea is just beginning. The development of anticancer treatments that are largely selective for the neoplastic clone has, until recently, remained an elusive goal. However, an expanding cadre of “targeted therapeutics” in clinical use illustrates the enormous potential of this approach. Genetic alterations in cancer in humans may involve gene activation, amplification, or inactivation or allelic haplodeficiency. These signature genetic features that are unique to the malignant clone can be exploited to develop treatments that are inherently tumor-specific. The concept of synthetic lethality originates from studies in drosophila model systems in which a combination of mutations in two or more separate genes leads to . . .